The mechanistic basis of prostate cancer progression is poorly understood, and therapeutic options in these settings are limited, and only marginally effective. The present Program Project application is a multidisciplinary team effort designed to address these needs by elucidating fundamental mechanisms of prostate cancer growth (i), and credentialing novel molecular therapies for advanced disease, in vivo (ii). Our approach focuses on a prostate cancer signaling 'network'important for disease progression. This network connects three fundamental pathways of cellular homeostasis: mitochondrial control of cell survival by molecular chaperones, pleiotropic signaling by integrin adhesion receptors, and local regulation of gene expression in bone metastasis. Project 1 (Altieri) will dissect the function of mitochondria-localized Heat Shock Protein-90 (Hsp90) chaperones in survival of prostate cancer cells, Project 2 (Languino) will study the mechanism of prostate cancer progression mediated by a{v}B{6} integrin, and Project 3 (Stein and Lian) will elucidate the mechanistic requirements of Runx2-dependent gene expression in metastatic prostate cancer to the bone. Each project embeds preclinical evaluation of a novel class of """"""""network inhibitors"""""""" in molecular and genetic models of localized and metastatic prostate cancer, in vivo. These agents include small molecule Hsp90 antagonists subcellularly targeted to mitochondria (Project 1), a function-blocking monoclonal antibody to a{v}B{6} (Project 2), and gene therapy silencing of Runx2 by short hairpin RNA (Project 3). All three projects are thematically integrated, rely on a long-standing track record of collaboration between the participating investigators, and share common experimental strategies, in vitro, and genetic disease models, in vivo. Three discovery-oriented Cores support equally the proposed experimental aims. Core A (Administration and Biostatistics: Altieri and Hsieh) will ensure programmatic integration, and provide biostatistics support for the preclinical studies. Core B (Animal Models: Bogdanov and Jones) will maintain quality control of the various genetic mouse models of prostate cancer, and provide state-of-the-art molecular imaging for analysis of tumor responses, in vivo. Core C (Pathology: Leav and Jiang) will oversee quantitative tissue analysis and evaluation of molecular biomarkers for pathway and target validation of """"""""network inhibitors"""""""", in vivo. The overall application is designed to merge molecular and translational prostate cancer research in a single, integrated and multidisciplinary platform. The overarching goal is to credential novel molecular therapies for patients with advanced and metastatic prostate cancer.

Public Health Relevance

Despite recent gains in the understanding of cancer genes and their pathways, advanced prostate cancer remains a deadly disease with no viable therapeutic options. The present application will unravel fundamental mechanisms of prostate cancer progression and characterize new agents as therapeutics for localized and disseminated disease. The results will pave the way for the introduction of novel molecular therapies for patients with advanced prostate cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wistar Institute
United States
Zip Code
Karpel-Massler, Georg; Ishida, Chiaki Tsuge; Bianchetti, Elena et al. (2017) Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses. Cancer Res 77:3513-3526
Bryant, Kelly G; Chae, Young Chan; Martinez, Rogelio L et al. (2017) A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy. Oncotarget 8:112184-112198
Zingiryan, Areg; Farina, Nicholas H; Finstad, Kristiaan H et al. (2017) Dissection of Individual Prostate Lobes in Mouse Models of Prostate Cancer to Obtain High Quality RNA. J Cell Physiol 232:14-8
Ishida, Chiaki Tsuge; Shu, Chang; Halatsch, Marc-Eric et al. (2017) Mitochondrial matrix chaperone and c-myc inhibition causes enhanced lethality in glioblastoma. Oncotarget 8:37140-37153
DeRita, Rachel M; Zerlanko, Brad; Singh, Amrita et al. (2017) c-Src, Insulin-Like Growth Factor I Receptor, G-Protein-Coupled Receptor Kinases and Focal Adhesion Kinase are Enriched Into Prostate Cancer Cell Exosomes. J Cell Biochem 118:66-73
Caino, M Cecilia; Seo, Jae Ho; Wang, Yuan et al. (2017) Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer. J Clin Invest 127:3755-3769
Kumar, Vinit; Donthireddy, Laxminarasimha; Marvel, Douglas et al. (2017) Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors. Cancer Cell 32:654-668.e5
Lu, Huimin; Wang, Tao; Li, Jing et al. (2016) ?v?6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor. Cancer Res 76:5163-74
Caino, M Cecilia; Seo, Jae Ho; Aguinaldo, Angeline et al. (2016) A neuronal network of mitochondrial dynamics regulates metastasis. Nat Commun 7:13730
Sayeed, Aejaz; Lu, Huimin; Liu, Qin et al. (2016) ?1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation. Oncotarget 7:52618-52630

Showing the most recent 10 out of 68 publications